title: Rapid and efficient cancer cell killing mediated by high-affinity death receptor homotrimerizing TRAIL variants.
abstract: The tumour necrosis factor family member TNF-related apoptosis-inducing ligand (TRAIL) selectively induces apoptosis in a variety of cancer cells through the activation of death receptors 4 (DR4) and 5 (DR5) and is considered a promising anticancer therapeutic agent. As apoptosis seems to occur primarily via only one of the two death receptors in many cancer cells, the introduction of DR selectivity is thought to create more potent TRAIL agonists with superior therapeutic properties. By use of a computer-aided structure-based design followed by rational combination of mutations, we obtained variants that signal exclusively via DR4. Besides an enhanced selectivity, these TRAIL-DR4 agonists show superior affinity to DR4, and a high apoptosis-inducing activity against several TRAIL-sensitive and -resistant cancer cell lines in vitro. Intriguingly, combined treatment of the DR4-selective variant and a DR5-selective TRAIL variant in cancer cell lines signalling by both death receptors leads to a significant increase in activity when compared with wild-type rhTRAIL or each single rhTRAIL variant. Our results suggest that TRAIL induced apoptosis via high-affinity and rapid-selective homotrimerization of each DR represent an important step towards an efficient cancer treatment.
authors.affiliation: Department of Pharmaceutical Biology, University of Groningen, The Netherlands.
authors.forename: C R
authors.initials: CR
authors.lastname: Reis
authors.forename: A M
authors.initials: AM
authors.lastname: van der Sloot
authors.forename: A
authors.initials: A
authors.lastname: Natoni
authors.forename: E
authors.initials: E
authors.lastname: Szegezdi
authors.forename: R
authors.initials: R
authors.lastname: Setroikromo
authors.forename: M
authors.initials: M
authors.lastname: Meijer
authors.forename: K
authors.initials: K
authors.lastname: Sjollema
authors.forename: F
authors.initials: F
authors.lastname: Stricher
authors.forename: R H
authors.initials: RH
authors.lastname: Cool
authors.forename: A
authors.initials: A
authors.lastname: Samali
authors.forename: L
authors.initials: L
authors.lastname: Serrano
authors.forename: W J
authors.initials: WJ
authors.lastname: Quax
mesh_terms: D019943:Amino Acid Substitution; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D017209:Apoptosis; D045744:Cell Line, Tumor; D019295:Computational Biology; D005260:Female; D006801:Humans; D007700:Kinetics; D009154:Mutation; D010051:Ovarian Neoplasms / Q000188:drug therapy; D011485:Protein Binding; D055503:Protein Multimerization; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000737:chemistry* / Q000235:genetics / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand